Soluble urokinase plasminogen activator receptor (suPAR) in the emergency department: An update

Background: The biomarker soluble urokinase plasminogen activator receptor (suPAR) is an indicator of inflammation which is increased in a variety of chronic and acute disease states. Its most promising application in the emergency setting is to aid in the prognostic stratification of patients by identifying those at high risk of deterioration. This is a narrative review of studies evaluating the use of suPAR. Methods: We conducted a Medline search for studies on the use of suPAR in patients acutely admitted to the emergency department. Results: 25 original studies were included in the review. suPAR as a marker of inflammation has been used alone or combined to other inflammatory biomarkers in the assessment of patients suffering from various acute and chronic diseases in an emergency setting. As it is non-specific, it may increase in infectious disease, malignancy or acute coronary syndromes among other conditions, but quantitative suPAR levels correlate with disease severity. It may be useful for the identification of high risk patients regardless of underlying pathology. Conclusion: As the ideal biomarker in the emergency setting has not been identified yet, suPAR may be a promising addition to the established biomarkers for the initial assessment of patients in this setting. Additional research is necessary to evaluate the usefulness of suPAR guided management algorithms.

S everal biomarkers involved in different biological pathways have been used in the emergency department setting aiming to help clinicians in the diagnosis, risk stratification and monitoring of diseases. Concentration of the soluble urokinase plasminogen activator receptor (suPAR) in serum is intimately related to the immune and inflammatory status of the patients, and has been used in the recent years in the assessment of several diseases with multiple underlying pathophysiological processes (1,2). The precursor protein of suPAR is expressed in various immune system cells and suPAR is released into the systemic circulation upon the activation of these cells. It is considered a non-specific biomarker as elevated plasma levels are encountered in a variety of both acute and chronic diseases apart from infection and sepsis, including malignant tumors, congestive heart failure and various autoimmune conditions (3). suPAR is a biomarker reflecting a low-grade inflammation, a mechanism that is present in the development of several diseases, such as infectious, cardiovascular, malignant diseases and more. Plasma levels of suPAR are also associated with social habits, such as smoking, alcohol consumption, and lifestyle (1,4). The suPAR level is indicative of immune system activity and inflammatory processes.
Although suPAR does not belong to the common used tools of investigation in daily practice, meets some basic criteria of a useful biomarker because it reflects various underlying pathophysiology, remains stable in plasma and is not significantly affected by the circadian cycle. Normal suPAR level in healthy individuals' plasma is below <3 ng/ml, in unselected patients in the emergency department 3-6 ng/ml, and in critically ill patients is > 6 ng/ml (2,5,6). Due to its lack of specificity, it is not particularly useful for diagnostic purposes, although low levels can be used in combination with other biomarkers to rule out possible causes for patients' complaints. Its most promising application is in the prognostic stratification of patients presenting to different medical settings, as measurements seem to correlate with disease severity and mortality. Previous research has focused on the use of suPAR as a prognostic marker in the inpatient, outpatient and intensive care setting where it proves to be predictive of mortality but the information it offers does not appear to influence clinical practice. It is predictive of mortality in acute coronary syndromes and marked suPAR elevation is commonly observed in septic shock. The purpose of this study is to evaluate the clinical value of suPAR in the emergency department setting, where clinicians are required to decide upon a course of action immediately while the underlying cause of the patients' complaints is initially unclear. Our hypothesis is that suPAR as a biomarker may be valuable for the early identification of patients with severe illness who require intensive care, regardless of the actual diagnosis. As it is not specific for a particular disease, we expect its value as an aid to the diagnostic process to be limited.
The identification of a biomarker with the highest validity for diagnosis, prognosis and management of patients in the emergency department remains of high priority. This is an update of the current literature regarding the role of suPAR as a diagnostic and prognostic biomarker when used in the setting of an acute care ward.

Methods
A Medline search was conducted and the search terms were 'suPAR' and 'Emergency Department'. After the selection of the most suitable articles to the research object, the bibliographies were reviewed, and additional relevant publications were extracted. We intended to include the use of suPAR as a prognostic indicator of patients admitted to the ED in the review cohort studies, regardless of the underlying diagnosis. Studies with a sample of at least 10 patients with initial evaluation in the emergency department and subsequent follow-up were to be included, likewise the provided relevant data to the use of suPAR as a prognostic indicator. Articles not relevant to the emergency setting, articles focusing exclusively on COVID-19 and articles not available in English were excluded. Though this was not a systematic review, a PRISMA flow chart is provided for the study ( figure 1). The results were current as of December 20, 2020. Institutional ethics review board approval was waived for this work as it did not involve human or animal subjects. The work is compliant with ethical standards as dictated by the 1975 declaration of Helsinki.

Results
The articles retrieved during the review process are presented in table 1 chronologically. The study population, main findings and conclusions of each study are listed, together with any additional notable comments. The role of suPAR as a prognostic and diagnostic biomarker has been investigated in large cohorts of patients admitted to the ED. In one article published in 2012, suPAR elevation was identified as an independent negative prognostic factor in patients with a variety of ailments (7). In 2016, in a retrospective study 4, 343 patients were enrolled and a strong correlation was found between elevated suPAR values and adverse outcomes, most notably mortality and subsequent ED admissions. suPAR measurements may provide important insight into disease prognosis, as adverse events were much more common in groups of patients with elevated suPAR on admission and conversely those with lower initial values were less likely to die or readmitted to the ED (8).
A study by the same group in 2018 consecutively enrolled 17, 312 admitted patients with the intention to investigate whether the prognostic accuracy of the National Early Warning Score (NEWS) could be improved by the addition of suPAR elevation to the scoring system. In this large cohort of patients, the suPAR-NEWS composite score could identify high and low risk groups of patients more accurately the NEWS score when used alone. Intriguingly, elevated suPAR measurements were associated with increased mortality even in patients for whom the NEWS score alone indicated a minimal risk of deterioration (9).
The interventional prospective trial (TRIAGE III) consecutively included 16,801 patients admitted to the ED to evaluate whether a triage system guided by suPAR measurements could affect mortality in the trial centers. Implementation of this system had no effect of mortality. The association between suPAR elevation and mortality was however noted in this cohort as well at multiple follow-up time points (10). Based on this trial, two further articles led to some more useful conclusions regarding suPAR. The first one, a post-hoc analysis of TRIAGE III trial indicated that suPAR measurements could more accurately discern a 7-day mortality risk when combined with routine triage processes (11). And the second one, another post-hoc sub-study, demonstrated that readily available suPAR measurements in the ED resulted in increased 24-hour discharge rates and shorter hospital stays at the cost of a higher rate of readmissions (12). This is in contrast with the findings of a previous study, which demonstrated that using suPAR to guide management in the ED did not lead to increased short-term readmissions (within the first few days), but was associated with a greater risk of readmission within a month after discharge (13). A pilot study regarding the use of suPAR for rapid prognostic stratification and triage in a resource limited setting showed promising results, but further data is warranted before suPAR guided algorithms could be incorporated into clinical practice (14). With regard to the assessment of SIRS patients in the ED, a study showed that among several studied biomarkers, suPAR was not superior to others (15). To the contrary of this study, the other ones indicated that suPAR could contribute to the prediction of bacteremia in SIRS patients (16), was found suitable to differentiate SIRS patients with and without positive blood cultures (17), was found the most promising biomarker among evaluation of nine biomarkers in early SIRS (18) and in the cases of early SIRS, suPAR plasma level was found predictive for mortality (19).
Furthermore, a study showed that elevated suPAR level predicts case fatality and severe sepsis in patients with suspected infection (20) and in a three -center Italian study, lactate and suPAR were the most accurate predictors of adverse outcomes for patients admitted to the emergency ward on suspicion of infection (21). Recently it has been suggested that there may be a correlation between suPAR elevation on ED admission and risk for both acute kidney injury during hospitalization and subsequent development of chronic renal failure (22). A large multicenter study suggested that suPAR may be predictive of complications of sepsis that may arise as a result of endothelial stress, including septic shock, renal failure and hepatic failure (23).
The role of suPAR has been examined in specific clinical conditions. In the exacerbation of chronic obstructive pulmonary disease (AECOPD), it was found that monitoring serum suPAR could be helpful in the assessment of treatment response and in the determination of the AECOPD prognosis (24). In cases of acute pancreatitis, had a significant value in indicating the severity of the acute disease (25) and in a retrospective study suPAR elevation was associated with an increased risk of emergency surgery and greater postoperative mortality during the first 3 months of follow-up (26). In regard to cardiac diseases, a study showed that suPAR could reliable predict mortality in patients with suspected acute myocardial infarction in the ED (27), but another article by the same group showed that circulating levels of suPAR on top of high sensitive troponin I (hs-TnI) do not improve the early diagnosis of AMI (28). This was also assessed in an article published in 2013, in which suPAR was used for prognostic stratification of patients presenting to the ED with acute chest pain and increased levels were associated with mortality (29).
Another notable cohort study included 22653 patients between 40 and 69 years old and 19889 individuals over the age of 70. Its primary purpose was to examine the validity of prognostic stratification models across a relatively wide age range. A suPAR measurement was available for 6400 individuals, demonstrating that it retained a relatively higher prognostic validity in middle age and younger patients compared with the geriatric subgroup (30). In another study that acutely admitted patients >65 years were assessed and results showed that suPAR measurements may have significant associations with organ dysfunction and physical performance status (31). Another prospective multi-center study of 136 geriatric individuals over age 75 who received emergency treatment for infection concluded that among several biomarkers (including suPAR), MR-proADM was the most reliable and accurate predictor of 30-day mortality (32).

Discussion
A body of literature has been identified in regard to the use of soluble urokinase plasminogen activator receptor in the emergency department setting. Most of the related studies have been performed for the last 15 years, demonstrating the possible role of suPAR in the prognostic stratification of a broad spectrum of diseases in acutely admitted patients (5). SuPAR elevation in the emergency department has been associated with increased acute mortality and an increased risk of complications in patients with sepsis, non-infectious SIRS and acute coronary syndrome and may aid in the identification of high-risk patients when used in conjunction with other biomarkers and common clinical criteria. Though suPAR is used as a biomarker in a variety of settings in tertiary canters in Scandinavian countries, there are certain concerns that limit its widespread adoption: it is considerably more expensive than other common tests utilized in the emergency setting as it is performed by enzyme-linked immunosorbent assay (ELISA) and to this point no standard reference range for normal values has been established (1). It is exquisitely non-specific, a characteristic which may be considered beneficial as it can be used by a variety of different specialists for the evaluation of different disease processes. This does however limit its value for the initial diagnosis of patients presenting to the emergency department and the interpretation of suPAR levels in patients with multiple comorbid conditions which are expected to elevate them is quite complex, especially in the absence of an evidence-based reference range. There is insufficient evidence to recommend the routine use of suPAR in the evaluation of acute chest or abdominal pain. Preliminary findings suggest that suPAR elevation may be correlated with higher mortality in patients with acute coronary syndromes, but it does not offer any advantage compared to the use of serial electrocardiograms (ECGs) and troponin measurements (27). There is insufficient data regarding its utility in the evaluation of abdominal pain (9). It may be most useful in the initial evaluation of sepsis, as the extremely elevated levels of suPAR are specific for septic shock and may aid in identifying patients who require prompts treatment in an intensive care setting (4).
In the emergency department setting a proper risk assessment of patients is necessary to ensure that the most ill of them are prioritized, quickly examined and received the most careful observation. For that reason, triage systems are used for this risk assessment aiming to prioritize the order of patients to be treated. suPAR is a novel biomarker closely related to the underlying immune and inflammatory status of the patient. High suPAR levels are associated to the presence and progression of a disease and related to increased mortality risk. However, although suPAR seems to correlate well with other common used inflammatory biomarkers, it is not yet feasible to use suPAR guided algorithms to guide management of patients in the emergency ward. Discharging patients on the basis of low suPAR score at this time poses an unacceptable risk of emergent complications outside of the hospital and readmission with a worse prognosis than upon initial presentation (2). An extremely elevated level of SuPAR could however facilitate a decision to initiate intensive care for a patient with suspected sepsis, which may consist of administration of fluids at a faster rate, central venous catheter placement, administration of different antibiotics consideration of intubation and mechanical ventilation. Thus, it is clear that it may be useful for the identification of patients at high risk of sepsis complications but low levels should not be interpreted as implying minimal risk. In other medical conditions that might be evaluated in the ED such as acute coronary syndromes or pancreatitis, it is not yet clear whether the addition of suPAR to other ubiquitous laboratory tests would change clinical practice in a meaningful way. Since suPAR is elevated in chronic disease as well, it may be difficult to ascertain in patients with multiple comorbidities whether an elevated suPAR measurement in the emergency setting is associated with a condition of acute onset or if it reflects the chronic disease burden of the patient. This is especially true for individuals suffering from malignant or autoimmune diseases which are associated with significant suPAR elevation. This could limit the usefulness of suPAR in this high-risk group if baseline levels are not available (1,2). An ideal biomarker would be expected to have near perfect sensitivity and specificity for the conditions it is used to evaluate, a quantitative correlation with disease severity and a measurement method which provides results in a timely manner which in the emergency room setting would be within a matter of minutes. No time lag would be expected to exist between the onset of the disease process and the elevation of the ideal biomarker levels above the diagnostic threshold. Based on the above description, the ideal biomarker does not exist for any condition, though troponin measurements for the evaluation of myocardial infarction are perhaps the test closest to this ideal.
Articles published during the past decade are encouraging regarding the prognostic validity of suPAR measurements in an emergency setting. It is however far from the ideal biomarker and the evidence remains is not sufficient to recommend the widespread adoption of suPAR guided management algorithms. An additional drawback is the fact that outside the Scandinavian region is Europe clinical experience with this test is extremely limited.
There is no doubt that multiple benefits will arise when a biomarker that is closer to the ideal is discovered for acutely admitted patients. These would include the reduction of wait times in the emergency department, the reduction of the number of re-admissions to hospital and a better stratification for the management of the patients. suPAR is elevated in a number of several diseases and this characteristic may be useful for the clinicians, when using suPAR alone or in combination to other specific biomarkers of diseases in the attempt to increase diagnostic and prognostic accuracy.
In conclusions suPAR may be useful in the assessment of ED patients admitted with various diseases in the rapid assessment, in the risk stratification and the determination of more intensive clinical assessment and monitoring care. Its prognostic and diagnostic validity needs further investigation with larger multicenter prospective cohort studies. As its value lies mostly in its correlation with adverse outcomes, further studies should focus on the use of suPAR in triage of patients presenting for emergency care where it may aid in the identification of patients at high risk of mortality who should be treated in an intensive care setting. There is little evidence in favor of suPAR guided algorithms in the management of specific complaints (chest or abdominal pain, dyspnea, fever) and at this point discharging patients on the basis of normal suPAR levels poses unacceptable risk. suPAR measurements could be more smoothly integrated in mainstream clinical practice if utilized in combination with other established prognostic and diagnostic biomarkers of sepsis. It should however be emphasized that laboratory tests or biomarkerguided algorithms are best utilized as an aid to management decisions which are first and foremost derived from a clinical evaluation of the patient. Evidence-based management algorithms and guidelines based on biomarkers may facilitate more effective management decision-making but they are not a substitute for clinical judgment. This is especially true for initial evaluation in the setting of emergency department.